Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival rates, many MB patients still die from their disease. Thus, novel and more effective therapies for MB are critically important. Among the four major subgroups of MB, MYC-driven (Group 3) MB has the worst prognosis and exhibits overexpression or amplification of the MYC oncogene; however, the etiology of Group 3 MB remains elusive. We recently developed a unique model of MYC-driven MB that originates from embryonic cerebellar cells, but the cell type from which the tumor arises is unclear. Stem cells have been the favored candidates for targets of transformation due to their capacity for self-renewal and proliferation. Sox2 expression has been identified in the embryonic cerebellar stem cells. Thus we hypothesize that Sox2+ cells serve as the origin of MYC-driven MB. Upon transformation, these cells may be responsible for tumor propagation and maintenance, thus targeted removal of this cell population may lead to tumor regression. In this proposal, we plan to use our mouse model to determine (1) whether normal Sox2+ cerebellar stem cells are tumor-initiating cells (cell of origin); (2) whether Sox2+ tumor cells are tumor- propagating cells (cancer stem cells); and (3) whether Sox2+ tumor cells are required for tumor maintenance and removal of these cells results in tumor regression. By successful completion of these studies, we hope to pave the way for novel strategies to target and eradicate tumor cells, thereby improving outcomes for patients with this disease.